Field
The present invention relates to certain substituted 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole and 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine compounds and derivatives of such compounds; pharmaceutical compositions containing them; methods of making them; and their use in various methods, including the inhibition of GlyT1, and the treatment of one or more disorders, including neurological disorders, psychotic disorders, dementia, and other conditions and diseases involving GlyT1.
Description of the Related Technology
The amino acid glycine has at least two important functions in the central nervous system (CNS). It acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors, and it also influences excitatory activity by acting as an essential co-agonist with glutamate for N-methyl-D-aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a more constant level and seems to modulate/control the receptor for its response to glutamate.
One way to control synaptic concentrations of neurotransmitters is to influence their re-uptake at the synapses. By removing neurotransmitters from the extracellular space, transporters can control their extracellular lifetime and thereby modulate the magnitude of the synaptic transmission (Gainetdinov et al., Trends in Pharm. Sci. 2002, 23, 367-373).
Glycine transporters, which form part of the sodium and chloride family of neurotransmitter transporters, play an important role in the termination of post-synaptic glycinergic actions and maintenance of low extracellular glycine concentration by reuptake of glycine into presynaptic nerve terminals and surrounding fine glial processes.
Two distinct glycine transporter genes have been cloned (GlyT1 and GlyT2) from mammalian brain which give rise to two transporters with about 50% amino acid sequence homology. GlyT1 presents four isoforms arising from alternative splicing and alternative promoter usage (1a, 1b, 1c and 1d). Only two of these isoforms have been found in rodent brain (GlyT1a and GlyT1b). GlyT2 also presents some degree of heterogeneity. Two GlyT2 isoforms (2a and 2b) have been identified in rodent brains. GlyT1 is known to be located in CNS and in peripheral tissues, whereas GlyT2 is specific to the CNS. GlyT1 has a predominantly glial distribution and is found not only in areas corresponding to strychnine sensitive glycine receptors but also outside these areas, where it has been postulated to be involved in modulation of NMDA receptor function (Lopez-Corcurera et al., Mol. Mem. Biol. 2001, 18, 13-20). Thus, one strategy to enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of the GlyT1 transporter (Bergereon et al., Proc. Mid Acad. Sci. USA 1998, 95, 15730-15734; Chen et al., J. Neurophysiol. 2003, 89, 691-703).
Glycine transporter inhibitors are suitable for the treatment of neurological and neuropsychiatric disorders. The majority of disease states implicated are psychoses, schizophrenia (Armer R. E. and Miller D. J., 2001, Exp. Opin. Ther. Patents, 11, 563-572), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorders and mood disorders associated with schizophrenia, (Pralong et al., Prog. Neurobiol., 2002, 67, 173-202), autistic disorders (Carlsson M. L., J. Neural Transm., 1998, 105, 525-535), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer R. E. and Miller D. J., Exp. Opin. Ther. Patents 2001, 11, 563-572).
Thus, increasing activation of NMDA receptors via GlyT1 inhibition may lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.
Glycine transport inhibitors are already known in the art, for example, as disclosed in: Intl. Pat. Appl. Publ. WO2010/010133 (Glaxo, Jan. 28, 2010) 2-Thia-1,3-diazaspirocyclic-substituted phenylacetamides; U.S. Pat. No. 7,589,089 (Hoffman-La Roche, Sep. 15, 2009) [(Arylcarbamoyl)methyl]arylamide derivatives; U.S. Pat. No. 7,538,114 (Amgen, May 26, 2009) Piperazineacetic acid derivatives; U.S. Pat. No. 7,951,836 (Hoffman-La Roche, May 31, 2011) Substituted phenyl methanone derivatives; U.S. Pat. No. 7,626,056 (Merck, Dec. 1, 2009) Cyclohexanesulfonyl derivatives; U.S. Pat. No. 8,124,639 (Pfizer, Feb. 28, 2012) Bicyclic [3.1.0] heteroaryl amides; Intl. Pat. Appl. Publ. WO2006/094843 (Glaxo, Sep. 14, 2006) N-benzoyl piperazines; U.S. Pat. No. 7,220,744 (Hoffman-La Roche, May 22, 2007) Benzoylpiperazine derivatives; U.S. Pat. No. 7,776,886 (Merck, Aug. 17, 2010) Cyclopropyl piperidine derivatives; Intl. Pat. Appl. Publ. WO2005/046601 (Merck, May 26, 2005) 4-Phenylpiperidine derivatives; U.S. Pat. No. 7,189,850 (Hoffman-La Roche, Mar. 13, 2007) Triaza-spiropiperidine derivatives; U.S. Pat. No. 7,462,617 (Hoffman-La Roche, Dec. 9, 2008) Acylpiperazine derivatives; U.S. Pat. No. 7,427,612 (Hoffman-La Roche, Sep. 23, 2008) 1-(2-Aminobenzoyl)-piperazine derivatives; U.S. Pat. No. 7,319,099 (Hoffman-La Roche, Jan. 15, 2008) Alkoxybenzoylpiperazines; and U.S. Pat. No. 6,710,071 (Pfizer, Mar. 23, 2004) Sarcosine difluoromethylene aromatic ether derivatives.
However, there remains a need for potent GlyT1 inhibitors with desirable pharmaceutical properties, such as those bearing on potency, specificity and side effect profiles. The present invention meets these and other needs in the art by disclosing substituted 2,4,5 ,6-tetrahydropyrrolo[3,4-c]pyrazole and 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine compounds as potent and well-tolerated GlyT1 inhibitors.